Obesity induced by high-fat diet promotes insulin resistance in the ovary

Akamine, Eliana Hiromi; Marçal, Anderson Carlos; Camporez, João Paulo; Hoshida, Mara Sandra; Caperuto, Luciana C.; Bevilacqua, Estela; Carvalho, Carla Roberta de Oliveira

doi:10.1677/joe-09-0461

Cited by 90 publications

(75 citation statements)

References 55 publications

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“…Egr-1 has previously been shown to play a key regulatory role in the ovulation process and localized to granulosa cells of preovulatory and antral follicles after human chorionic gonadotropin stimulation in normal-weight rats (14). Prior studies by Akamine et al (2) and Nteeba et al (39) established that long exposure to high-fat diet in both rats and mice can lead to a similar reduction in PI3K and Akt phosphorylation in whole ovarian tissue, as seen in the current study compared with lean controls. Results from the present study demonstrate that insulin signaling may be affected by obesity; however, additional studies leveraging insulin challenges or hyperinsulinemic euglycemic clamps are warranted to confirm whether ovaries are insulin resistant in this model (2,66).…”

Section: Discussionmentioning

confidence: 99%

Maternal obesity is associated with ovarian inflammation and upregulation of early growth response factor 1

Ruebel

Shankar

Gaddy

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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A. Maternal obesity is associated with ovarian inflammation and upregulation of early growth response factor 1. Am J Physiol Endocrinol Metab 311: E269 -E277, 2016. First published June 7, 2016 doi:10.1152/ajpendo.00524.2015.-Obesity impairs reproductive functions through multiple mechanisms, possibly through disruption of ovarian function. We hypothesized that increased adiposity will lead to a proinflammatory gene signature and upregulation of Egr-1 protein in ovaries from obese (OB; n ϭ 7) compared with lean (LN; n ϭ 10) female Sprague-Dawley rats during the peri-implantation period at 4.5 days postcoitus (dpc). Obesity was induced by overfeeding (40% excess calories for 28 days) via total enteral nutrition prior to mating. OB dams had higher body weight (P Ͻ 0.001), greater fat mass (P Ͻ 0.001), and reduced lean mass (P Ͻ 0.05) and developed metabolic dysfunction with elevated serum lipids, insulin, leptin, and CCL2 (P Ͻ 0.05) compared with LN dams. Microarray analyses identified 284 differentially expressed genes between ovaries from LN vs. OB dams (Ϯ1.3 fold, P Ͻ 0.05). RT-qPCR confirmed a decrease in expression of glucose transporters GLUT4 and GLUT9 and elevation of proinflammatory genes, including CCL2, CXCL10, CXCL11, CCR2, CXCR1, and TNF␣ in ovaries from OB compared with LN (P Ͻ 0.05). Protein levels of PI3K and phosphorylated Akt were significantly decreased (P Ͻ 0.05), whereas nuclear levels of Egr-1 (P Ͻ 0.05) were increased in OB compared with LN ovaries. Moreover, Egr-1 was localized to granulosa cells, with the highest expression in cumulus cells of preovulatory follicles. mRNA expression of VCAN, AURKB, and PLAT (P Ͻ 0.05) correlated with %visceral fat weight (r ϭ 0.51, Ϫ0.77, and Ϫ0.57, respectively, P Յ 0.05), suggesting alterations in ovarian function with obesity. In summary, maternal obesity led to an upregulation of inflammatory genes and Egr-1 expression in peri-implantation ovarian tissue and a concurrent downregulation of GLUTs and Akt and PI3K protein levels.early growth response factor 1; gene expression; inflammation; obesity; reproduction IN THE US, 60% OF WOMEN OF REPRODUCTIVE AGE are either overweight or obese, which predisposes them to higher risk of infertility and pregnancy complications (12,21,57,59,60) and potentially leads to adverse effects on offspring development. Higher adiposity leads to hormonal dysregulation, decreased primordial follicle numbers at the initiation of follicular development, lower ovulation rates, a reduced number of cleaved blastocysts developing to eight cell stage and reduced implantation rates, and ultimately impaired reproductive function (11,16,17,22,33,35,61). Similarly, in experimental models, obesity leads to decreased primordial and preovulatory follicle numbers, increased follicular atresia and changes in steroidogenesis via decreased steroidogenic acute regulatory protein, and increased Cyp11a1 protein content in ovarian tissue (7,16,23,37,38,53,61). Evidence of lipid accumulation, endoplasmic reticulum stress, and oxidative stress in ova...

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Section: Discussionmentioning

confidence: 99%

Maternal obesity is associated with ovarian inflammation and upregulation of early growth response factor 1

Ruebel

Shankar

Gaddy

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

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“…These results together indicated that FoxO3a may be an important regulatory factor involved in the ovarian follicular development of HFD-fed mice. Obesity is currently the major factor that causes type 2 diabetes, cardiac malformation and infertility (1). With the increasing epidemic of obesity, a useful mouse model of obesity is essential for studying the mechanisms that underlie the negative effects of obesity negatively on the function of the ovary.…”

Section: Discussionmentioning

confidence: 99%

“…Obesity is associated with high rates of type 2 diabetes mellitus, cardiovascular disease and infertility (1,2). The Nurses' Health study reported that a high body mass index (BMI) value is associated with a high risk of infertility in women (3).…”

Section: Introductionmentioning

confidence: 99%

“…The Nurses' Health study reported that a high body mass index (BMI) value is associated with a high risk of infertility in women (3). Furthermore, obesity is an important factor involved in polycystic ovary syndrome, a condition associated with anovulatory infertility (1,(4)(5)(6). However, the molecular mechanism of the effect of obesity on follicular development remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Effect of high-fat diet-induced obesity on the Akt/FoxO/Smad signaling pathway and the follicular development of the mouse ovary

Zhang

Liao

et al. 2016

Molecular Medicine Reports

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Abstract. Obesity has a negative effect on ovarian functions, which is reported to increase the risk of infertility. The mechanism underlying obesity-induced infertility is not yet clear. The present study established a high-fat diet (HFD)-induced obesity mouse model to elucidate the mechanisms underlying the effect of HFD-induced obesity on follicular development in the mouse ovary. The 4-week-old female mice were fed with HFD or normal control (NC) diet for 15 or 20 weeks. Body mass index was used to demonstrate that the mice were obese following HFD treatment. The follicular development of the ovaries from the HFD group mice was retarded in a time-dependent manner, as demonstrated by morphological and histological examination of the ovaries. Further investigation via western blot analysis demonstrated that the activity of the transcription factor, forkhead box O3a (FoxO3a), was increased by HFD through downregulated FoxO3a phosphorylation, which may contribute to the inhibited development of ovarian follicles. To determine the regulatory mechanism of FoxO3 on the follicular development, the expression levels of FoxO3a target protein, Smad1/5/8, were also determined and there was significant decrease in phosphorylated Smad1/5/8 in the ovaries from the HFD group compared with the NC group, indicating that FoxO3a/Smad1/5/8 may be important in the regulation of follicular development. The expression levels of the upstream regulator of FoxO3a, Akt, were also examined and it was demonstrated that Akt phosphorylation was significantly reduced in the HFD group compared with the NC group, indicating that Akt/FoxO3a may be also involved in follicular development. Together, the experiments demonstrated that HFD-induced obesity affected the activity of the Akt/FoxO3a/Smad1/5/8 signaling pathway in a time-dependent manner during the follicular development of the mouse ovary, leading to abnormal follicular development. These findings may provide part of a theoretical basis for the clinical prevention and treatment of obesity-associated female infertility.

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“…As a case in point, increased insulin levels have been associated with increased prolactin secretion 96 and decreased growth hormone secretion pulses 97 . Furthermore, studies using a diet-induced insulin resistance rat model have found increased insulin and progesterone levels 98 . Also, we have previously reported the co-regulated expression levels of insulin, growth hormone, leptin and cortisol in first onset schizophrenia patients, using a targeted analyte cluster method which detects patterned behavior 99 .…”

Section: Effects On the Insulin Signalling And The Hpa Axis In Schizomentioning

confidence: 99%

Os efeitos do estresse na função do eixo hipotalâmico-pituitário-adrenal em indivíduos com esquizofrenia

Guest

Martins-de-Souza²,

Rahmoune

et al. 2012

Arch. Clin. Psychiatry (São Paulo)

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Over the last few decades, evidence has been emerging that the pathogenesis of psychiatric disorders such as schizophrenia can involve perturbations of the hypothalamic-pituitary-adrenal (HPA) axis. Variations in the manifestation of these effects could be related to the differences in clinical symptoms between affected individuals as well as to differences in treatment response. Such effects can also arise from the complex interaction between genes and environmental factors. Here, we review the effects of maternal stress on abnormalities in HPA axis regulation and the development of psychiatric disorders including schizophrenia. Studies in this area may prove critical for increasing our understanding of the multi-dimensional nature of schizophrenia. Further research in this area could ultimately lead to the development of improved diagnostics and novel therapeutic approaches for treating this debilitating psychiatric condition.Guest FL, et al. / Rev Psiq Clín. 2013;40(1):20-7 Keywords: Psychiatric disorders, schizophrenia, HPA axis dysfunction, diagnosis, biomarkers. ResumoNas últimas décadas, têm surgido evidências sugerindo que a patogênese de desordens psiquiátricas, tais como a esquizofrenia, pode envolver perturbações no eixo hipotalâmico-pituitário-adrenal (HPA). Variações na manifestação desses efeitos poderiam estar relacionadas a diferenças em sintomas clínicos entre os indivíduos afetados, assim como a diferenças na resposta ao tratamento. Tais efeitos podem também ser originados de complexas interações entre genes e fatores ambientais. Aqui, revisamos os efeitos do estresse maternal em anormalidades na regulação do eixo HPA e desenvolvimento de desordens psiquiátricas, incluindo a esquizofrenia. Estudos nessa área podem gerar o aumento do nosso entendimento da natureza multidimensional da esquizofrenia. Posterior pesquisa nesse campo poderia, em última instância, levar ao desenvolvimento de melhores diagnósticos e novas abordagens terapêuticas para essa debilitante condição psiquiátrica.Guest FL, et al. / Rev Psiq Clín. 2013;40(1):20-7 Palavras-chave: Desordens psiquiátricas, esquizofrenia, disfunção do eixo HPA, diagnóstico, biomarcadores.

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Obesity induced by high-fat diet promotes insulin resistance in the ovary

Cited by 90 publications

References 55 publications

Maternal obesity is associated with ovarian inflammation and upregulation of early growth response factor 1

Maternal obesity is associated with ovarian inflammation and upregulation of early growth response factor 1

Effect of high-fat diet-induced obesity on the Akt/FoxO/Smad signaling pathway and the follicular development of the mouse ovary

Os efeitos do estresse na função do eixo hipotalâmico-pituitário-adrenal em indivíduos com esquizofrenia

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